(a) Field of the Invention
The present invention relates to peptides derivatives of desArg9-bradykinin (desArg9-BK) which act as agonists at kinin B1 receptors and their use as therapeutic agents.
(b) Description of Prior Art
Emerging findings suggest that the kallikrein-kinin system may play key position in blood pressure regulation and organ protection (Hagiwara et al., 2004, Hypertens Res 27(6), 399-408; Couture and Girolami, 2004, Eur J Pharmacol 500 (1-3), 467-485). Kinins are a group of bioactive peptides formed by numerous tissues and within the blood. Kinins can be divided in two major subgroups of naturally occurring peptides namely bradykinin (BK), kallidin (LysBK), [Hyp3]-BK and Lys[Hyp3]-BK and their respective bioactive metabolites produced by carboxypeptidases M and N (alias kininases I), desArg9BK, LysdesArg9BK, [Hyp3]-desArg9BK and Lys[Hyp3]-desArg9BK. Actions of bradykinin and congeners and desArg9-related peptides are relayed via specific receptors referred to as B2 and B1, respectively, which are ubiquitously expressed on cell membranes in the affected tissues. Kinin B2 and B1 receptors are found in a variety of cells as endothelia, smooth muscles, epithelia, white blood cells. They mediate vascular smooth muscle relaxation via release of autacoids, particularly from the endothelium. This function provides the basic mechanism of peripheral vasodilatation which is responsible for a large part of their in vivo hypotensive effect (Duka et al., 2006, Am J Physiol Endocrinol Metab [Epub ahead of print]).
Contrary to B2 receptors which are constitutively expressed, the B1 receptors are usually not found in physiological conditions but is induced by various stimuli (i.e. cytokines) in several cell types including vascular endothelial and smooth muscle cells, fibroblasts, neurons. Inducible B1 receptors are involved in various types of vascular inflammation associated with diabetic, hypertensive conditions, and angiogenesis. The beneficial and protecting roles of kinin B1 receptors in cardiovascular-related physiopathology have been recently reviewed (Couture and Girolami, vide supra). The induction of B1 receptor and subsequent activation may be seen as self-defense mechanism elicited by the vasculature against recurrent deleterious ischemic/hypoxic episodes. This view is supported by several lines of evidence. Exogenous perfusion of naturally-occurring B1 receptor agonist desArg9BK prior ischemic conditions, in a Langerdorff setup, decreased arrhythmias (Chahine et al., 1993, Brit J Pharmacol 108, 318-322) and protected endothelial functions in coronary arteries in the follow-up reperfusion process (Bouchard et al., 1998, Brit J Pharmacol 123, 413-420). In addition, systemic supplementation of a stable desArg9BK-related analogue caused a reparative angiogenesis in a murine of limb ischemia (Emanueli et al., 2002, Circulation 105, 360-366). The involvement of newly expressed B1 receptors in reparative angiogenesis of wounded arteries was equally seen in an animal model of balloon angioplasty (Pruneau et al., 1994, Brit J Pharmacol 111, 1029-1034; Agata et al., 2000, Hypertension 36, 364-370). Also, the important role of B1 receptors in preservation of cardiac function after myocardial infarction has recently been demonstrated using kinin B1 receptor gene knockout mice (Xu et al., 2005, Hypertension 45, 747-753)
These salutary actions, within macro- and micro-vascular networks, lies in part on capacity of kinins including desArg9-BK derivatives to promote the release of nitric oxide and prostaglandins, which may serve as cytoprotective, angiogenic and dilatory factors thereby preserving functions and oxygenation of vital organs (Kichuk et al., 1996, Circulation 94, 44-51; Emanueli et al. vide supra; Sharma and Thani, 2004, IDrugs 7, 926-934). However, naturally-occurring B1 receptor agonists LysdesArg9BK and desArg9BK as many other endogenous peptide hormones, are subjected to rapid proteolysis by tissue and plasma enzymes, which limit their therapeutic potential (Rhaleb et al., 1990, Brit J Pharmacol 99, 445-448; Drapeau et al., 1991, J Pharmacol Exp Ther 259, 997-1003). There is therefore a need for metabolically stable and potent compounds with long duration of action capable of selectively activating B1 receptors which interestingly, are not prone to desensitization after exposure with their cognate ligands. Compounds of the present invention may be pharmacologically exploited for post-ischemic healing (Couture and Girolami, vide supra; Emanueli et al. vide supra; Hagiwara et al. vide supra; Duguay et al., 2004, Brit J Pharmacol 141(4), 728-736; Emanueli and Madeddu, 2001, Trends Pharmacol. Sci. 22(9), 478-484; Parenti et al., 2001, FASEB J 15(8), 1487-1489).